The discovery and increased understanding of the function of antimicrobial peptides (AMPs) has revolutionized classical concepts of immune defense. AMPs act to protect against infections by direct antimicrobial action on microbes and by altering the host inflammatory response. The production of AMPs must be carefully regulated since disease can occur from either too little expression or abnormally high AMP production. In this application we wish to understand how expression of cathelicidin and other antimicrobial peptides are controlled, an important question for human health in light of prior studies showing abnormal production contributes to the pathophysiology of skin diseases such as atopic dermatitis, rosacea and psoriasis. The specific aims of this application are as follows: Specific Aim 1: Define the mechanism and role of PTH/PTHrP in control of cathelicidin expression and skin infections. Specific Aim 2: Understand the impact of hypoxia and role of HIF in the cathelicidin response. Specific Aim 3: Define the cell-specific roles of cathelicidin in immune defense. These aims will be accomplished by a combined approach of synergistic PIs, pairing mammalian immunology, genetic and biochemistry platforms with endocrinology and microbial genetics and infectious disease models. Preliminary data described in this application strongly support the novel and unexpected hypothesis that underlie Aims 1 and 2, and Aim 3 will be accomplished by the first use of the Cre-loxP system to target cathelicidin in mice. This system will provide a new tool through with the role of cell- specific cathelicidin can be understood. By learning how to control cathelicidin expression we will provide a new diagnostic and therapeutic tool and better understand the complex interactions between innate host immunity and our microbial environment.